CN1777416B - 含有乳酸根的药物组合物及其用途 - Google Patents
含有乳酸根的药物组合物及其用途 Download PDFInfo
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Abstract
本发明涉及含有250至2400毫摩尔/升乳酸根或乳酸、2至10毫摩尔/升钾阳离子及任选的2至5毫摩尔/升钙阳离子的药物组合物。本发明还涉及该组合物的药物用途。本发明还涉及具有250至2400毫摩尔/升乳酸或乳酸根浓度的组合物的药物用途。
Description
本发明涉及含有乳酸根的药物组合物、制备该药物组合物的方法以及该组合物的多种医药和治疗用途。具体而言,本发明涉及药物组合物及其在治疗疾病及紊乱、例如心血管疾病、脑紊乱、器官衰竭、肥胖症、由药物和手术引起的急性血液动力学窘迫、败血症性休克或肥胖症中的用途。在一个具体方面,本发明还涉及高渗乳酸根溶液在治疗脑紊乱中的用途。
已经发现乳酸本身或其阴离子的形式——乳酸根阴离子或其盐——相当广泛地应用于药学领域。传统上乳酸根阴离子在透析用的组合物中用作缓冲剂,参见例如Chung等,Perit.Dial.Int.2000,20Suppl.5:S57-67或美国专利US 6,610,206。乳酸根还是Ringer氏乳酸盐中的成分,Ringer氏乳酸盐与人血液等张(含有130mmol/l Na+、5.4mmol/l K+、1.85mmol/l Ca2+、27mmol/l乳酸根及112mmol/l Cl-),它在血容量不足中用作生理盐水溶液供静脉内输注。此外,在美国专利US 5,100,677中已经将乳酸根描述为可用于液体疗法的永久性单阴离子代谢物,选自丙酮酸根、乳酸根、d-β羟基丁酸根、乙酰乙酸根。根据该发明,含有0.01至2400mmol/lL-乳酸根的溶液适合于胃肠道外、口服、透析及输注疗法。可根据该美国专利治疗的病症的具体实例有酸中毒、脱水、血液电解质缺失、休克、营养不良及尿毒症。
近来,乳酸根阴离子还已经成为研究经受心脏手术的患者方面的课题。在该研究中,在经受选择性冠状动脉旁路移植术(CABG)的术后患者中研究了1M高渗乳酸根溶液(每升由90g乳酸根及23g钠组成)的代谢及血液动力学作用(Mustafa,I.和Leverve,X.M.Shock,18,306-310,2002)。由该研究,作者作出了如下结论:高渗乳酸根溶液在经受这类手术的患者中是安全的,并且可被很好地耐受。
但是,尽管这些结果是有希望的,但仍然期望有易于生产、易于使用并且适合于大量治疗应用的含有乳酸根的组合物。因此,本发明的一个目的是提供这样的组合物。
除了其它手段,该目的通过具有各独立权利要求的特征的药物组合物而得以解决。这样的组合物是含有250至2400毫摩尔/升乳酸或乳酸根及2至10毫摩尔/升钾的药物组合物。此外,本发明还涉及高渗乳酸根组合物、即具有250至2400毫摩尔/升乳酸或乳酸根浓度的组合物在治疗脑紊乱、例如创伤性脑损伤、脑缺血或非创伤性脑损伤中的用途。因此,用于治疗这些脑紊乱的适宜的药物组合物可以仅含特定浓度范围内的乳酸根或乳酸作为唯一(药学活性)组分,即它可以不含钾。
本发明基于如下出人意料的结果:含有乳酸根的高渗组合物(包含例如本文所述浓度的乳酸根作为活性成分的组合物)在如此多的治疗适应症、例如治疗由创伤性脑损伤引起的颅内血压(ICP)升高或脑水肿或者治疗由例如多器官损伤、休克或术后状况引起的急性血液动力学窘迫中,具有大量的应用及高度的有效性。
在本发明的优选实施方案中,乳酸或乳酸根阴离子的浓度为每升约350至约2000mmol,或约400至约1500mmol,或500至约1500毫摩尔。在其它优选的实施方案中,乳酸或乳酸根阴离子的浓度为约800至约1200毫摩尔/升。在某些实施方案中,已经发现约500或约1000毫摩尔/升的乳酸或乳酸根浓度是特别适宜的。但是,根据具体的应用以及病症的严重性和所治疗的个体,在250至2400mmol/L内任何适宜的乳酸根浓度均可被选择。因此,该范围内的任何乳酸根浓度、例如350、500、800或2200mmol乳酸根均可与可存在于本发明的组合物中的其它成分的任何浓度组合使用,例如在2至10毫摩尔/升内的任何钾浓度或者在约2至约5毫摩尔/升内的钙浓度(见下文)。
在此方面还应当指出:术语“乳酸根”包括两种对映异构形式,即D-乳酸根和L-乳酸根,其中优选L-乳酸根。但是,只要D-乳酸根以对所治疗患者没有不良或甚至是毒性影响的量存在时,在本发明中就还可使用L-和D-乳酸根的混合物。因此,术语“乳酸”还包括D-乳酸和L-乳酸,并且还包括乳酸的多聚或寡聚形式,例如聚乳酸(聚乳酸根)。此外,术语“乳酸”的意思还包括乳酸衍生物、例如乳酸酯类。这些酯类的实例有乳酸甲酯、乳酸乙酯或者乳酸与多元醇、例如用于命名其中某些的甘油的酯类等。此外,乳酸、乳酸衍生物(例如其酯类)以及乳酸根的混合物的用途也包括在本发明的范围内,即药物组合物可以含有乳酸、聚乳酸及乳酸根。
如果使用乳酸根,为了实现本发明的组合物的电中和(特别是当组合物作为液体存在时),组合物中还存在阳离子,例如铵、二甲基铵、二乙基铵、钠或这些阳离子的混合物。在一些实施方案中,优选钠用作乳酸根阴离子的抗衡离子,即在那些情况下,钠的浓度与选定的乳酸根的浓度相同。因为此原因,乳酸钠是用于制备本发明的组合物所优选的化合物。如果使用乳酸,则不需要存在其它阳离子(由乳酸解离产生的质子或H3O+除外)以实现电中和。但是,如果在本发明中使用乳酸作为活性成分,则除乳酸以外可酌情存在如下文所述的生理学上有用的阳离子。
此外,该组合物还含有钾。已经发现为了预防由单独使用高渗乳酸钠治疗而可能导致的低钾血,钾的存在是特别有用的。在本发明的组合物的一些实施方案中,钾的浓度为2.5至6毫摩尔/升,在一些实施方案中,本文优选约3.5mmol或约4mmol/L浓度的钾。
本发明的组合物还可以含有钙浓度为约2至约5毫摩尔/升的钙。在本发明的组合物的一些使用钙的实施方案中,本文优选2.5至4毫摩尔/升的钙浓度。2.7毫摩尔/升的浓度特别适合于某些应用。已经发现在特定浓度范围内的可代谢的乳酸根阴离子与钙离子的组合可有效地增强患者的血液动力学功能。例如,乳酸根与钙的组合存在可显著增强心脏的收缩(归因于正性肌力作用)。此外,该组合在体循环和肺血管形成中可松弛紧张性(血管阻力降低),这可引起例如心输出量显著增加,甚至是在心脏衰竭患者中亦如此(参见实施例3)。在此方面应当指出:本文所述的组合物具有显著的抗缺血/抗氧化作用,由此可用于改善缺血再灌注损伤后的受累患者的恢复(参见实施例4)。在本文中,还应当指出:本发明的组合物还具有显著的容积作用(补充液体),这使得它对于需要输注液体来复苏的患者而言成为引人注目的药物。出人意料的是,这种容积作用强于已知的晶体溶液如甘露醇溶液的血液动力学作用。已经证明:仅需要已知溶液体积的50至70%就可获得相同的血液动力学作用(参见实施例2)。这种减少使患者治疗的应激显著减小,例如因为必须通过肾脏净化的液体较少或者因为产生肿胀及水肿的风险降低。因此,本发明的组合物能够显著减少治疗可能的副作用。最后,已经出人意料地发现:在急性颅内压升高时(由脑创伤引起),本发明的组合物能够显著降低颅内压。已经发现这种增加比迄今为止用于这种紊乱的标准治疗--甘露醇的作用更加显著并且时间更长(参见实施例2)。
除了上文所述的组分外,本发明的组合物一般还包含氯离子(Cl)作为钾和钙阳离子的带负电的抗衡离子。
按照上文的公开内容,本发明的组合物优选作为水溶液使用。
在本文的一个特别优选的实施方案中,本发明的组合物含有上文提到的以下浓度的成分:
1000毫摩尔/升乳酸根,
9.4毫摩尔/升氯离子(Cl),
4毫摩尔/升钾(K),
2.7毫摩尔/升钙(Ca),以及
1000毫摩尔/升钠(Na)。
在本文的另一个特别优选的实施方案中,该组合物含有以下浓度的这些成分:
1000毫摩尔/升乳酸根,
8.9毫摩尔/升氯离子(Cl),
3.5毫摩尔/升钾(K),
2.7毫摩尔/升钙(Ca),以及
1000毫摩尔/升钠(Na)。
在本文的其它特别优选的实施方案中,在组合物中使用以下浓度:500毫摩尔/升乳酸根,
8.9至9.4毫摩尔/升氯离子(Cl),
3.5至4毫摩尔/升钾(K),
2.7毫摩尔/升钙(Ca),以及
500毫摩尔/升钠(Na)。
此外,本文优选的实施方案的另一个实例是具有以下浓度的组合物:750毫摩尔/升乳酸根,
8.9至9.4毫摩尔/升氯离子(Cl),
3.5至4毫摩尔/升钾(K),
2.7毫摩尔/升钙(Ca),以及
750毫摩尔/升钠(Na)。
组合物还可含有其它成分,例如其它与生理学有关的阳离子,如镁或锌。镁可以以至多约3或4mmol/升的浓度存在。除了这些与生理学相关的阳离子或者与这些阳离子的存在无关,该组合物还可含有磷酸根。可将磷酸根以任何适宜的形式、例如作为一氢或二氢磷酸盐加入。适宜的磷酸盐的实例有NaH2PO4和Na2HPO4。如果存在磷酸根时,一般采用至多5mmol/升的浓度。还可以以至多约5mmol/升的浓度加入本发明的组合物的另一种化合物是ATP。ATP可以以其镁盐的形式使用。
可包含在组合物中的其它适宜的添加剂是起渗透作用的药剂(渗透剂和膨胀剂),因此,它们还可增加本发明的组合物的渗透作用。这些渗透剂和膨胀剂的实例包括碳水化合物、明胶、血清蛋白如白蛋白或其混合物。适合的碳水化合物的实例有山梨糖醇、木糖醇、葡萄糖、聚葡萄糖、变性淀粉及未变性淀粉如羟乙基淀粉(HES)或者这些碳水化合物的混合物。这些碳水化合物通常可以以至多约10%(w/v)的浓度存在。例如,羟乙基淀粉的一般浓度为6%(w/v)。如果选择另一种膨胀剂如明胶作为添加剂,则它一般以至多约3.5%或4%的量存在。
如已经提到的,本发明的组合物可用于大量各种治疗应用中。例如,它可用于治疗选自冠状动脉疾病(coronary diseases)、脑紊乱、器官衰竭、肥胖症以及由内科和手术引起的急性血液动力学窘迫的疾病或病症。该组合物还可用于患者的复苏及手术/术后治疗。因此,本发明的组合物可作为在重症监护病房(ICU)中的药物以及对肥胖或分解代谢亢进的患者作为胃肠道外的食物补充来用于急诊病例(例如,如在下文所详细讨论的用于治疗颅内压升高)。
特别感兴趣的一个治疗应用是本发明的药物组合物在治疗脑紊乱中的用途。在这种情况下,在本发明的组合物中仅需存在有乳酸根和/或乳酸。
这些脑紊乱的实例有创伤性脑损伤、脑缺血或非创伤性脑损伤、与脑功能障碍有关的代谢紊乱以及与手术有关的并发症。
在一个实施方案中,创伤性脑损伤为闭合性或开放性颅脑创伤(CCT)。令发明人吃惊的是,发现本发明的药物组合物不仅能够显著降低由创伤性脑损伤引起的颅内压(ICP)升高,而且其效力超过了甘露醇的效力,甘露醇是降低ICP升高的标准渗透治疗方法。
此外,本发明的组合物还可施用于罹患非创伤性脑损伤、例如中风或冷损伤(cold-lesion)的患者或施用于患有与脑功能障碍有关的代谢紊乱、例如肝昏迷或低血糖性昏迷的患者。由于本发明的组合物具有强的渗透作用,因此它还可用于治疗由创伤性或非创伤性脑损伤(紊乱)引起的任何(细胞内)脑水肿,以减少或预防这种水肿。
可用本发明的组合物来治疗的心血管疾病或冠状动脉疾病的实例有用以命名其中一些的心肌缺血、心脏功能障碍、糖尿病的心血管并发症、急性梗塞、缺血再灌注损伤或动脉硬化并发症。
由于组合物通常起抗缺血作用,因此它还可用于治疗罹患任何器官衰竭的患者。可被治疗的器官衰竭的具体实例包括但不限于肾衰竭、肝衰竭或心衰竭。此外,还可能用本发明的组合物例如来治疗由心衰竭引起的心源性休克。
还已经发现本发明的组合物可用于治疗任何形式的急性血液动力学窘迫。这种急性应激例如可由多器官损伤、术后状况、败血症性休克、呼吸系统疾病或急性呼吸窘迫综合征所引起。
根据上文的公开内容,本文所公开的组合物通常作为液体施用。为此目的,给患者施用液体的任何适宜方式均可使用。优选组合物以胃肠道外的方式通过输注或注射施用(例如通过静脉内、肌内或皮内施用)。对于静脉内施用,本发明的组合物可作为单次快速静脉输液或单次快速静脉注射液来提供。乳酸根的一般最大日剂量为约4.5至7.5mmol/kg体重/天,或者以70kg体重计算为0.315至0.525mol乳酸根/天。如果使用含有500mM乳酸根的本发明的组合物来治疗如本文所述的患者,则可使用3至5ml溶液/kg体重的剂量、在15至20分钟内通过单次快速静脉输注来施用4.5mmol/kg体重/天的量。当然还可以使用其它剂量,这取决于具体的病症和所治疗的患者。对于治疗中风,含有500mM乳酸根的组合物的一般剂量为10ml溶液/kg体重/小时,即5mmol/kg体重/小时。因此,如果使用1M乳酸根溶液,可以以5ml/kg体重/小时的速率输注相同量的乳酸根。如果在本发明的组合物中采用聚乳酸根,则口服施用为优选的途径。
本发明还涉及制备药物组合物的方法,该组合物含有250至2000毫摩尔/升乳酸或乳酸根、2至10毫摩尔/升钾及2至5毫摩尔/升钙(如果存在的话)。
在一个优选的实施方案中,该方法包括提供各自量的乳酸钠或乳酸、氯化钾和任选的氯化钙以及将这些化合物溶解于可药用的溶剂中。在此方面可以指出:制备本发明的液体组合物所必需的成分、例如乳酸钠、乳酸、氯化钙及氯化钾还可作为固体来混合,然后仅在给需要其的患者施用前将该混合物溶解于可药用的溶剂中。因此,固体形式的、包含乳酸根或乳酸以及钾(还有任选的任何其它成分,例如钙或镁或渗透剂)的药物组合物也在本发明的范围之内。在某些情况下,例如当贮藏室受到限制时,制备本发明的组合物组分的固体混合物并仅在需要时制备其液体形式甚至可能是有利的。
原则上讲,产生具有所需含量的组合物的化合物的每个适宜组合均可用于制备本发明的组合物。例如,组合物可由乳酸、乳酸钠、氯化钙(×2H2O)及氯化钾来制备。或者,还可使用乳酸钙、乳酸钠及氯化钠的混合物来制备本发明的组合物。
溶剂可以是任何适宜的可药用溶剂,例如,水或水与有机溶剂如乙醇的混合物,只要这种溶剂能够以规定量溶解固体组分、特别是组合物的组分。溶剂一般为去离子水、单蒸水或双蒸水或者微过滤水,其纯度在药物应用上是可以接受的。如此制备的液体组合物还可在给患者施用前例如通过加热灭菌或过滤除菌进行处理。用于制备本发明的组合物的优选的溶剂/药物载体的一个实例是如美国药典(USP)分类的无菌注射用水(WFI)。
本发明还通过附图及随后的非限制性实施例来说明。
图1表明与正在用常规甘露醇疗法进行治疗的12名同样罹患脑创伤的患者组(空心正方形)相比,在接受本发明的组合物输注后,12名罹患脑创伤的患者组(实心正方形,含有500mmol/l乳酸根、9.4mmol/lCl、4mmol/l K、2.7mmol/lCa及500mmol/lNa)的颅内压的变化。
图2表明与已经接受用甘露醇进行的治疗的12名患者组相比,用本发明的组合物治疗的12名罹患脑创伤的患者组的存活率。
图3表明与常规甘露醇治疗(实心条形)相比,用本发明的组合物治疗的血液摩尔渗透压浓度的变化以及血液中血细胞比容(Hte)及血红蛋白(Hb)浓度(空心条形)的变化。
图4表明与已经接受用甘露醇治疗的患者组(实心条形)相比,用本发明的组合物治疗的12名罹患脑创伤的患者组(空心条形)的脑灌注压的变化。
图5表明与同样包含110名个体的患者对照组施用Ringer氏乳酸盐(空心正方形)相比,当给110名心脏手术后的患者施用本发明的组合物时,本发明的组合物(含有500mmol/l乳酸根、9.4mmol/l Cl、4mmol/l K、2.7mmol/lCa及500mmol/l Na,空心圆形)对平均动脉压(MAP,图5A)、心率(HR每分钟跳动次数,图5B)、心脏指数(CI,图5C)及全身血管阻力指数(SVRI,图5D)的影响,
图6表明与施用Ringer氏乳酸盐的作用相比,给110名心脏手术后的患者施用该组合物对肺血管阻力指数(PVRI)的作用。
图7表明与施用Ringer氏乳酸盐的作用相比,给110名心脏手术后的患者施用该组合物对毛细血管肺楔压的作用。
图8表明与输注Ringer氏乳酸盐的总体积(空心条形)相比,给110名患者输注本发明的高渗乳酸根组合物的总体积(实心条形)以及两组中每组110名患者的排尿量(图8A)、液体平衡(图8C),而图8D、E和F表明与Ringer氏乳酸盐(空心正方形)相比,在给术后患者输注本研究所用的组合物(空心圆形)的过程中,血红蛋白(Hb)含量(图8D)、乳酸根的血液浓度(图8E)及钠的浓度(图8F)。图8G表明接受含有乳酸钠的本发明的组合物(2.5mmol/kg体重,15分钟;空心条形)或含有氯化钠的组合物(2.5mmol/kg体重,15分钟;实心条形)输注的每组40名患者的两组中,氯离子血液浓度(mmol/L)的变化(输注前后)。
图9表明与含有5.5mM葡萄糖及0.2mM己酸的灌注介质[对照]相比,在缺血体外模型(预灌注的大鼠心脏)中,乳酸根(在灌注介质中5mM,实心正方形)对心率血压乘积(RRP,图9A)、舒张压(图9B)及心率(每分钟跳动次数)的影响。
实施例1:药物组合物的制备
具有浓度为500mmol/L乳酸根、9.4mmol/L氯离子(Cl)、4mmol/L钾(K)、2.7mmol/L钙(Ca)及500mmol/L钠(Na)的500升组合物(可产生1008mmol/L的摩尔渗透压浓度)使用L-乳酸钠溶液(50重量%)、CaCl2×2H2O(96.5%纯度)、KCl(99.85%纯度)和注射用水如下来制备:
将400kg注射用水装入温度为30至40℃的灭菌混合罐中。然后,在搅拌下连续加入103.6kg氯化钙、56.2kg乳酸盐溶液及150kg氯化钾。在成分加入完成后,于38℃另外继续混合45分钟。然后,加入剩余的56.60kg注射用水,以产生具有上文提到的浓度的组合物。
实施例2:治疗由脑创伤引起的颅内压升高
在本研究中,将实施例1中制备的药物组合物(含有500mmol/L乳酸根、9.4mmol/L氯离子(Cl)、4mmol/L钾(K)、2.7mmol/L钙(Ca)及500mmol/L钠(Na))用于治疗罹患脑损伤(脑创伤)的患者。本研究包括其群体数据见于表1的罹患严重头部损伤的患者(Glasgow昏迷评分(GCS)≤9或脑计算机X射线断层摄影(CT)扫描异常),如果患者显示颅内压(ICP)≤20mmHg(这被认为是有生命危险的),则用上文提到的组合物或常规甘露醇溶液(20%w/v)进行治疗。为此目的,给每组12名的患者组施用(输注)本发明的组合物或甘露醇,每15分钟测定ICP。如果患者的ICP升至30mmHg或降低未大于5mmHg,则交换治疗,也就是说,如果用甘露醇治疗患者失败,则患者按照本发明输注高渗乳酸根溶液,反之亦然。
表1:所治疗患者的群体数据(平均值±sem.)
用甘露醇治疗的组 | 用高渗乳酸根治疗的组 | |
年龄(岁) | 35±4 | 39.6±4.9 |
重力评分(IGS II) | 43.8±3.6 | 48.7±2.6 |
GCS | 5.4±0.5 | 5.2±0.5 |
CT扫描(TDB) | 3±0.2 | 5.2±0.5 |
ICH发生 | 25 | 26 |
GCS=Glasgow昏迷评分,ICH=颅内高压
在本研究中,12名患者用甘露醇或本发明的高渗乳酸根溶液进行治疗,其结果显示在图1至4及表2至5中。
表2:治疗结果
用甘露醇治疗的组,n=11 | 用高渗乳酸根治疗的组,n=13 | |
存活数 | 11名中有7名 | 13名中有12名 |
交叉数 | 11名中有4名 | 13名中有6名 |
治疗成功数(所有治疗) | 25名中有14名 | 26名中有19名 |
治疗成功数(仅第一次治疗) | 11名中有5名 | 13名中有11名 |
表3:治疗前后的颅内压(ICP)及CPP
用甘露醇治疗的组,n=25 | 用高渗乳酸根治疗的组,n=26 | |
治疗前的ICP(mmHg) | 31±1.8 | 31.9±2.5 |
治疗后的ICP(mmHg) | 25.7±1.7** | 25.2±1.9** |
治疗前的CPP(mmHg) | 67.6±2.2 | 65.8±2.3 |
治疗后的CPP(mmHg) | 73.2±2.4 | 72.3±2.3 |
**p≤0.01(配对T-检验,治疗前后同组内比较)
表4:
用甘露醇治疗的组,n=25 | 用高渗乳酸根治疗的组,n=26 | |
治疗前的渗透压(mosm/kg) | 299±2.6 | 298.5±1.6 |
治疗后的渗透压(mosm/k/kg) | 302±2.5** | 300.0±1.9** |
治疗前的动脉The(%) | 32.7±1.1 | 32.0±0.9 |
治疗后的动脉The(%) | 31.6±1.1** | 31.0±0.9 |
**p≤0.01(配对T-检验,治疗前后同组内比较);##p≤0.01(配对T-检验,治疗前后同组内比较)
如在图1中所说明的,施用甘露醇和本发明的0.5M乳酸根溶液(它示范性地用来表明含有250mmol/l至2400mmol/l乳酸根或乳酸的高渗乳酸根溶液的效能)使颅内压在治疗后的头30分钟内降低约20%。但是,尽管甘露醇显示出一般已知的反跳作用,也就是说,ICP在治疗后的3.5小时内稳定上升至初始未经治疗的ICP的约90%,但是出乎发明人意料的是,ICP在施用高渗乳酸根溶液后的头30分钟后进一步降低,由此表明用高渗乳酸根溶液治疗具有延长作用。同样,如在图4中所表明的,施用本发明的乳酸根溶液可使脑灌注压发生较大变化(图4,还可见表3)。
本文发现的0.5M乳酸根溶液在降低ICP方面的这种延长且增加的效能进一步提供了重要的优点。即这样甚至可能应用第二个0.5M乳酸根溶液剂量而没有任何并发症来进一步降低ICP并由此可继续治疗——这用标准甘露醇治疗几乎是不可能的。根据在降低ICP方面较好的行为,用本发明的0.5M乳酸钠溶液治疗的12名患者中,有11名从脑创伤中存活下来,而用常规甘露醇治疗则仅有7名患者能被救活(图2,表2)。图3和表4表明与甘露醇治疗相比,使用这样的高渗乳酸根溶液还具有其它优点。血液摩尔渗透压浓度变化大于1%而达到大于101%的值归因于甘露醇的应用,而血液摩尔渗透压浓度变化仅0.5%归因于施用相同摩尔渗透压浓度的本发明的1M乳酸钠溶液。这里指出:可以认为总的变化较小。但是,变化的约50%的相对差异(当从由甘露醇引起的增加的角度考虑时)是显著的,特别是当使用本发明的乳酸根溶液时摩尔渗透压浓度的较小升高仍然会使ICP有很大降低时。这也可以从图3和表4中血细胞比容和血红蛋白值的测定看出。对甘露醇治疗而言,这些值的降低大于3%而达到初始值的97%,表明血液由于甘露醇输注而被相当显著地稀释。与其相比,并且不管有效性提高,应用相同体积的0.5M乳酸钠仅使血细胞比容及血红蛋白水平降低至约98.5%。这表示高渗乳酸根、例如0.5M溶液(或如本文规定的在250至2000mM内的任何其它浓度)没有这种稀释作用,而且更重要的是只需施用较少的输注液体。这从而表示对于已经被创伤性脑损伤严重影响和虚弱的患者而言,由额外的液体吸收引起的副作用显然是较低的。这从而也伴有由治疗引起的低得多的脑水肿风险(进一步)。
不希望被理论所限制,发明人相信:与甘露醇相比,乳酸根的优点是由不同的作用模式引起的。甘露醇不能进入受影响的脑细胞并且不被代谢。因此,甘露醇仅通过渗透作用来发挥其作用,即,只要血流-细胞外室内的渗透压高于ICP,水就会由于渗透压差从细胞内室流入细胞外室,并由此流入血流-细胞外室。当甘露醇通过尿从血流中被移除时,渗透压差变小,使水逆流返回至细胞室中,从而产生已知的反跳作用。在此方面还可以指出:完全依赖这种渗透压差就是甘露醇通常仅能被施用2次的原因,因为通过每次应用,血液和脑的渗透压差变小。与此相反,发明人相信:乳酸根在应用后的约头4小时内,通过任何含有线粒体的细胞、包括在脑中的脑细胞而被吸收和代谢。但是,仅乳酸根阴离子被代谢(代谢途径的终产物为二氧化碳和水),而各自的抗衡离子、例如钠则留在细胞外液中。为了实现电中和,氯离子和水一起被转运出细胞间隙。这种作用在40名患者的两组中(见图8G)中被证明,在患者组中研究了输注等摩尔量的乳酸钠和氯化钠(2.5mmol/kg BW,在15分钟内)后对血浆氯离子浓度的影响。与乳酸钠组相比,氯化钠组中血液氯离子浓度升高较大。但是,输注乳酸钠后氯离子浓度同样显著升高,表明氯离子是从细胞内液流向细胞外液,因为对于乳酸钠而言没有输注氯离子。因此,当应用本发明的高渗乳酸根组合物时,细胞水分的损失归因于细胞摩尔渗透压浓度的损失。因此没有反跳作用,从而也为给予乳酸根的第二个剂量提供了可能性。最后,可以指出:体内乳酸根阴离子减少和钠浓度升高另外在预防酸中毒方面是有用的。
实施例3:心脏手术后患者的术后治疗
实施例1中所使用的组合物还用于经受了选择性冠状动脉旁路移植术(CABG)的术后患者的复苏。本研究包括110名个体,将组合物的有效性与Ringer氏乳酸盐组合物之一(130mmol/l Na+、5.4mmol/l K+、1.85mmol/lCa2+、27mmol/l乳酸根及112mmol/l Cl)进行比较。输注进行6小时,其中所输注液体的体积通过医学人员来调整,以使平均动脉压(MAP)、中心静脉压(CVP)、心脏指数及肺毛细血管楔压(PCWP)维持在预定值。
由本研究得到以下结果。在输注本发明的高渗乳酸根溶液和常规的Ringer氏乳酸盐之间,平均动脉压(mmHg)和心率(每分钟跳动次数)的测定没有显示出任何显著的差异(见图5A和5B)。但是,当输注0.5M乳酸根溶液时,以测定每分钟每平方米体表面积的心脏泵血量来计算的心脏指数(CI)显著升高(图5C)。同时,以测定全身血管床对血流的阻力或障碍来计算的全身血管阻力(SVRI)在输注的6小时内降低(图5D)。这表示:输注本发明的组合物在术后治疗中不仅使心脏工作较好并由此使患者稳定,而且还使血流阻力降低,产生综合的积极协同作用。此外,如在图6中所说明的,由肺血管阻力指数(PVRI,测定肺血管床对血流的阻力或障碍)可明显地看出,输注本发明的高渗溶液还会使肺血管阻力显著降低,这使得本发明的组合物对于罹患病症如急性(或成人)呼吸窘迫综合征(ARDS)、急性肺损伤(ALI)、间质性肺疾病(ILD)或严重急性呼吸综合征(SARS)的患者的复苏和治疗而言是一种非常适宜的方法。此外,还通过监测毛细血管肺楔压(CPWP)评价了患者的充盈度(filling)。如在图7中所表明的,两个患者组在输注各自溶液的过程中的CPWP相同,表明患者的充盈度功效相同。
图8说明了本发明的组合物与Ringer氏乳酸盐相比的其它优点。与所需的2000ml Ringer氏乳酸盐相比,对于本发明的组合物而言,输注总体积在心脏手术后的头12小时内显著减少(约1200ml)(图8A),而12小时后患者的排尿量几乎等于约1800ml(图8B)。结果,对于用本发明的高渗乳酸根溶液输注的患者而言,液体平衡为负数(图8C),这表示从而可例如引起器官功能障碍的出现水肿的风险显著降低。本发明的组合物的这种性质是特别有利的,因为在手术过程中通常需要大体积的液体(例如Ringer氏乳酸盐)来维持患者的平均动脉压(MAP),结果患者在术后总是出现水肿。因此,本发明的组合物不仅可以减少水肿(或出现水肿的风险),而且同时也不会降低患者的血液动力学状态。
为了测定体内的液流,测定血液中的血红蛋白含量。如在图8D中所说明的,在输注本发明的高渗乳酸根组合物的过程中,血红蛋白含量降低,而对于施用Ringer氏乳酸盐而言,血红蛋白含量保持不变。因为两个患者组的出血状态和输血没有差别,这种在输注乳酸根组合物的过程中的弱的稀释作用产生于液体从周围组织向血流的转移。在此方面,可以指出:如在图8E中所表明的,在接受本发明的高渗乳酸根组合物的组中,血液中乳酸根浓度(血液乳酸根水平)仅在手术治疗后的头6小时内、即仅在输注乳酸根组合物的过程中是较高的。此外,如在图8F中所表明的,当输注本发明的乳酸根组合物时,血液中钠的浓度处于正常浓度范围内。与此相反,施用Ringer氏乳酸盐组合物伴有低于正常生理浓度的钠血液浓度。
实施例4:乳酸根用于治疗缺血的适宜性
为了测定乳酸根用于治疗例如缺血再灌注的病症的适宜性,将所分离的大鼠心脏用含有5mM乳酸根的灌注介质或用含有0.2mM己酸及5.5mM葡萄糖的灌注介质(对照)按照GarnierA.等人,J Mol Cell Cardiol 1996,28,1671-1682中所述的方案进行灌注。
从图9可以看出:大鼠心脏分离40分钟后(为了模拟缺血),与对照相比,灌注乳酸根40分钟使心率血压乘积(图9A)和心率(图9C)有显著较高和延长的增加。此外,如在图9B中所表明的,与对照相比,经输注乳酸根溶液,舒张压显著降低,这表明通过施用乳酸根溶液,心脏的减压得到了很大改善,从而预防或逆转“石心”的形成。因此,这些数据证明:本文所述的高渗乳酸根溶液可有利地用于治疗例如缺血再灌注损伤、心肌缺血或任何其它形式的心脏功能障碍。
Claims (19)
1.组合物在制备用于治疗脑水肿的药物组合物中的用途,所述的组合物含有400至1500毫摩尔/升L-乳酸或L-乳酸根、2至5毫摩尔/升钙以及2.5至6毫摩尔/升钾,其中脑水肿由创伤性或非创伤性脑损伤引起,其中钠用作L-乳酸或L-乳酸根的抗衡离子并且氯用作钾的抗衡离子。
2.组合物在制备用于治疗创伤性脑损伤的药物组合物中的用途,所述的组合物含有400至1500毫摩尔/升L-乳酸或L-乳酸根、2至5毫摩尔/升钙以及2.5至6毫摩尔/升钾,其中创伤性脑损伤是闭合性或开放性颅脑创伤,其中钠用作L-乳酸或L-乳酸根的抗衡离子并且氯用作钾的抗衡离子。
3.组合物在制备用于治疗非创伤性脑损伤的药物组合物中的用途,所述的组合物含有400至1500毫摩尔/升L-乳酸或L-乳酸根、2至5毫摩尔/升钙以及2.5至6毫摩尔/升钾,其中非创伤性脑损伤是中风或冷损伤,其中钠用作L-乳酸或L-乳酸根的抗衡离子并且氯用作钾的抗衡离子。
4.组合物在制备用于患者术后治疗的药物组合物中的用途,所述的组合物含有400至1500毫摩尔/升L-乳酸或L-乳酸根、2至5毫摩尔/升钙以及2.5至6毫摩尔/升钾,其中钠用作L-乳酸或L-乳酸根的抗衡离子并且氯用作钾的抗衡离子。
5.权利要求4的用途,其中术后治疗是对经受冠状动脉旁路移植术的患者的治疗。
6.权利要求1的用途,其中创伤性脑损伤是闭合性或开放性颅脑创伤。
7.权利要求1的用途,其中由创伤性或非创伤性脑损伤引起的颅内压升高被降低。
8.权利要求2的用途,其中由创伤性脑损伤引起的颅内压升高被降低。
9.权利要求3的用途,其中由非创伤性脑损伤引起的颅内压升高被降低。
10.权利要求1的用途,其中非创伤性脑损伤是中风或冷损伤。
11.权利要求1-10中任一项的用途,其中乳酸或乳酸根的浓度为500至1500毫摩尔/升。
12.权利要求11的用途,其中乳酸或乳酸根的浓度为800至1200毫摩尔/升。
13.权利要求12的用途,其中乳酸或乳酸根的浓度为1000毫摩尔/升。
14.权利要求1至10中任一项的用途,其中钙浓度为2.5至4毫摩尔/升。
15.权利要求1至10中任一项的用途,其中组合物为水溶液。
16.权利要求1至10中任一项的用途,其中组合物具有如下浓度:
1000毫摩尔/升乳酸根,
9.4毫摩尔/升氯离子,
4毫摩尔/升钾,
2.7毫摩尔/升钙,以及
1000毫摩尔/升钠。
17.权利要求1至10中任一项的用途,其中组合物具有如下浓度:
1000毫摩尔/升乳酸根,
8.9毫摩尔/升氯离子,
3.5毫摩尔/升钾,
2.7毫摩尔/升钙,以及
1000毫摩尔/升钠。
18.权利要求1至10中任一项的用途,其中组合物具有如下浓度:
500毫摩尔/升乳酸根,
9.4毫摩尔/升氯离子,
4毫摩尔/升钾,
2.7毫摩尔/升钙,以及
500毫摩尔/升钠。
19.权利要求1至10中任一项的用途,其中组合物具有如下浓度:
500毫摩尔/升乳酸根,
8.9毫摩尔/升氯离子,
3.5毫摩尔/升钾,
2.7毫摩尔/升钙,以及
500毫摩尔/升钠。
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